The 7-acylindolin-2-ones prepared by the process of this invention are useful in the preparation of 2-amino-3-acylphenylacetic acids and esters, salts and hydrates thereof. Preferably, the novel process of this invention is used in the preparation of 7-benzoylindolin-2-ones. The 7-benzoylindolin-2-ones are intermediates in a novel route to produce 2-amino-3-benzoylphenylacetic acids starting with indoline or 4-, 5- or 6-substituted indolines. The reaction sequence of this route is indolines.fwdarw.7-benzoylindolines.fwdarw.7-benzoylindoles.fwdarw.7-benzo yl-3-halo-indoles.fwdarw.7-benzoylindolin-2-ones.fwdarw.2-amino-3-benzoylph enylacetic acids. The 2-amino-3-benzoylphenylacetic acids are disclosed in U.S. Pat. Nos. 4,045,576 and 4,126,635. These compounds possess valuable pharmacological properties and are useful as pharmaceutical agents. They particularly exhibit excellent anti-inflammatory activity.
U.S. Pat. Nos. 4,045,576 and 4,126,635 disclose methods for the preparation of 7-benzoylindolin-2-ones. According to one method, 1-aminoindolin-2-one is reacted with a phenylacetone to give a 1-(.alpha.-methylphenethylindenimino) indolin-2-one which is cyclized in ethanolic hydrogen chloride to an ethyl .alpha.-(2-methyl-3-phenylindol-7-yl)acetate. This indolylester is treated with ozone in acetic acid solution to give an ethyl 2-acetamido-3-benzoylphenylacetate which is hydrolyzed and cyclized in dilute mineral acid to a 7-benzoylindolin-2-one.
Alternatively, these patents disclose that an ethyl .alpha.-(2-methyl-3-phenylindol-7-yl)acetate may be hydrolyzed in aqueous basic solution to an .alpha.-(2-methyl-3-phenylindol-7-yl) acetic acid which is treated with ozone in acetic acid solution to give a 2-acetamido-3-benzoylphenylacetic acid. The acid is hydrolyzed and cyclized in dilute acid to the 7-benzoylindolin-2-one.
U.S. Pat. No. 3,897,451 also discloses a method of preparing indolin-2-ones. Under this procedure, N-chloro-aniline is reacted with .beta.-thiocarboxylic ester to form an azasulfonium salt which is treated with a substantially anhydrous base to form an ortho-[(thioalkyl)(alkylthiocarbonyl)methyl]aniline. This ortho-substituted aniline is heated or acidified to form 3-thioalkyl-indolin-2-one which is desulfurized to form the indolin-2-one.
U.S. Pat. No. 3,975,531 discloses the preparation of 7-benzoylindolin-2-ones by (a) cyclization of 2-acetamido-3-benzoylphenylacetic acid or ethyl 2-acetamido-3-benzoylphenylacetate or (b) by reacting aminobenzophenones with alkyl .alpha.-(methylthio)acetates to give alkyl 2-amino-3-benzoyl-.alpha.-(methylthio)phenylacetates which are then cyclized and demethylthiolated to produce the 7-benzoylindolin-2-one.
These prior art methods are suitable for use in the preparation of 7-benzoylindolin-2-ones. However, these methods either produce low yields or must be conducted at low temperatures making them undesirable for large scale operation.
It is an object of this invention to provide novel methods for the preparation of 7-acylindolines, 7-acyl-3-halo-indoles and 7-acylindolin-2-ones.
It is a further object of this invention to provide novel 7-acylindoles and 7-acyl-3-halo-indoles.
Additional objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter from the following description of invention, the best mode of carrying out the invention, and the examples thereof.